Is FOXC1 p.Ser290Phe (c.869C>T) pathogenic?

FOXC1 p.Ser290Phe (c.869C>T) is classified Uncertain significance in FOXC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-19). AlphaMissense: likely benign (0.1237); Ultra-rare (popmax 0.0157%, amr); Associated with Axenfeld-Rieger syndrome type 3.

What condition is associated with FOXC1 p.Ser290Phe (c.869C>T)?

FOXC1 p.Ser290Phe (c.869C>T) is associated with Axenfeld-Rieger syndrome type 3, anterior segment dysgenesis 3 (ClinVar).

How common is FOXC1 p.Ser290Phe (c.869C>T) in the general population?

FOXC1 p.Ser290Phe (c.869C>T) is ultra-rare (popmax 0.0157%, amr) (gnomAD).

What do computational predictors say about FOXC1 p.Ser290Phe (c.869C>T)?

AlphaMissense predicts likely benign (score 0.1237) — an in-silico prediction, not a clinical call.

FOXC1 p.Ser290Phe

c.869C>T · rs775681400 · VCV1351505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 3

Computational evidence

Protein change
AlphaMissense	0.1237	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.68, phastCons 0.13
Regional constraint	o/e 1.21	unconstrained · MANE · 1,130 bp · p 2.5e-07 · regional, not allelic
Overall
CADD	18.92	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0157% Admixed American · 6/38,328 alleles

Filtering AF 0.0068% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00458%

Overall 0.000851% 12/1,409,662 alleles · ultra-rare exomes 8/1,264,414 · genomes 4/145,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0157%	6,388
Remaining individualsnot grpmax-eligible	0.00188%	53,100
European (non-Finnish)	0.000462%	216,216

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FOXC1
Protein: p.Ser290Phe
Coding: c.869C>T
MANE Select: NM_001453
dbSNP: rs775681400
Type: single nucleotide variant
Location: chr6:1611314 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.09
Residue 290: the 'disordered' region; the 'required for transcriptional inhibition' region

Full FOXC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Axenfeld-Rieger syndrome type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: anterior segment dysgenesis 3

Similar variants

FOXC1 p.Ser290= Uncertain significance ★ same residue
FOXC1 p.Ser290Ala Uncertain significance ★ ⚠ same residue
FOXC1 p.Ser290Tyr Uncertain significance ★ ⚠ same residue
FOXC1 p.Arg127His Pathogenic ★★ same condition
FOXC1 p.Arg127Leu Pathogenic/Likely pathogenic ★★ same condition
FOXC1 p.Arg170Trp Pathogenic ★★ same condition
FOXC1 p.Cys135Tyr Likely pathogenic ★★ same condition
FOXC1 p.Gln106Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/foxc1-p-ser290phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown